Leptin and the systems neuroscience of meal size control.

Abstract

The development of effective pharmacotherapy for obesity will benefit from a more complete understanding of the neural pathways and the neurochemical signals whose actions result in the reduction of the size of meals. This review examines the neural control of meal size and the integration of two principal sources of that control--satiation signals arising from the gastrointestinal tract and CNS leptin signaling. Four types of integrations that are central to the control of meal size are described and each involves the neurons of the nucleus tractus solitarius (NTS) in the dorsal hindbrain. Data discussed show that NTS neurons integrate information arising from: (1) ascending GI-derived vagal afferent projections, (2) descending neuropeptidergic projections from leptin-activated arcuate and paraventricular nucleus neurons, (3) leptin signaling in NTS neurons themselves and (4) melanocortinergic projections from NTS and hypothalamic POMC neurons to NTS neurons and melanocortinergic modulation of vagal afferent nerve terminals that are presynaptic to NTS neurons.

[Top] Intraoral glucose (10%) intake for chronic decerebrate (CD) and control rats did not differ as a function of the neurological condition of the rat. Intraperitoneal administration of the GLP-1R agonist exendin-4 [Ex-4] at 1.2 and 3.0 μg/kg suppressed intake significantly in both control and CD rats, compared with respective vehicle intakes. The suppression of intake by peripheral Ex-4 was not statistically different between control and CD rats, indicating that forebrain processing and forebrain-caudal brainstem communication is not necessary for the intake suppression triggered by peripheral GLP-1 receptor stimulation. *, P < 0.05 from respective vehicle.[Bottom] For control and CD rats, ip administration of Ex-4 (1.2 and 2.4 μg/kg) significantly suppressed 5 min gastric emptying of 0.9% saline, compared with vehicle in similar fashions. The gastric-emptying rates for the vehicle condition for control and CD rats did not statistically differ.

A significant proportion of leptin-responsive cells respond to gastric distension. A representative merged microphotograph of double IHC (P-STAT3 and c-Fos) from gastric distension combined with leptin-treated rats is shown on the left. On the right are shown high magnifications (top, P-STAT3 green fluorescence IHC; middle, c-Fos red fluorescence IHC; bottom, merged microphotograph from the double IHC) of the area marked on the left. Examples of double-labeled cells are shown in yellow. cc, Central canal. Scale bars, 200 μm.

Leptin delivered to the hindbrain is sufficient to amplify the intake-suppressive effects of an otherwise ineffective volume of gastric distension. Cumulative chow intake was not affected by either 4-ml gastric distension or icv leptin treatment alone at 30, 60, or 90 min. However, when combined, gastric distension and leptin significantly suppressed cumulative intakes at 60 and 90 min compared with results from the vehicle/sham-distension condition. *, P < 0.05.

(A) Increasing hindbrain AMPK activity (4th icv AICAR) reversed the suppression of cumulative food intake at 2h and 4h following 4th icv leptin administration. (B) In ad libitum fed rats, 4th icv administration of leptin (5μg) suppressed pAMPKα levels in NTS-enriched tissue (DVC) 2h after 4th icv administration compared to control injections. This suppression in pAMPKα levels in the DVC was reversed by 4th icv administration of AICAR, at a dose that was without effect on its own. (C) Conversely, no alterations in pAMPKα levels were observed in hypothalamic lysates by 4th icv administration of leptin, AICAR, or their combination, thus indicating a hindbrain site of action for the 4th icv administered compounds.* = P<0.05 from respective vehicle intakes.

10 pmol MTII stimulation of medullary raphe MC4-Rs produces hyperthermia in both intact rats (a) and chronic decerebrate rats (b). Line graphs represent across-rat average parameter measurements through the 8-h recording period. The bracketed time period on the line graph x-axis indicates the periods used in the histograms. Histograms in represent 6-h means + SEM. *, P < 0.05.